rs751286389

Variant names:

• chr1-243489015-C-A
• rs751286389
• NM_006642.5:c.1987C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-243489015-C-A
• chr1-243489015-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006642.5(SDCCAG8):​c.1987C>A​(p.Leu663Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L663L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDCCAG8 NM_006642.5 missense, splice_region
• Scores: Splicing: ADA: 0.2067
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80
• Publications: 1 publications found

Genes affected

SDCCAG8 (HGNC:10671): (SHH signaling and ciliogenesis regulator SDCCAG8) This gene encodes a centrosome associated protein. This protein may be involved in organizing the centrosome during interphase and mitosis. Mutations in this gene are associated with retinal-renal ciliopathy. [provided by RefSeq, Oct 2010]

AKT3 (HGNC:393): (AKT serine/threonine kinase 3) The protein encoded by this gene is a member of the AKT, also called PKB, serine/threonine protein kinase family. AKT kinases are known to be regulators of cell signaling in response to insulin and growth factors. They are involved in a wide variety of biological processes including cell proliferation, differentiation, apoptosis, tumorigenesis, as well as glycogen synthesis and glucose uptake. This kinase has been shown to be stimulated by platelet-derived growth factor (PDGF), insulin, and insulin-like growth factor 1 (IGF1). Alternatively splice transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

AKT3 Gene-Disease associations (from GenCC):

• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P
• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae)
• megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• microcephaly

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1958304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDCCAG8	NM_006642.5	c.1987C>A	p.Leu663Ile	missense_variant, splice_region_variant	Exon 17 of 18	ENST00000366541.8	NP_006633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDCCAG8	ENST00000366541.8	c.1987C>A	p.Leu663Ile	missense_variant, splice_region_variant	Exon 17 of 18	1	NM_006642.5	ENSP00000355499.3
SDCCAG8	ENST00000435549.1	c.1090C>A	p.Leu364Ile	missense_variant, splice_region_variant	Exon 10 of 11	1		ENSP00000410200.1
AKT3	ENST00000336199.9	c.*7-565G>T		intron_variant	Intron 13 of 13	1		ENSP00000336943.5
SDCCAG8	ENST00000497459.1	n.66C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250474 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461100 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726866

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		1.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.26
Sift	Benign	0.15	T;T
Sift4G	Benign	0.15	T;D
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.29		Gain of methylation at K668 (P = 0.0548);.;
MVP		0.55
MPC		0.27
ClinPred		0.88	D
GERP RS		3.4
Varity_R		0.089
gMVP		0.063
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.21
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751286389; hg19: chr1-243652317;